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Details for Patent: 7,713,999

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Details for Patent: 7,713,999

Title:Thrombin receptor antagonists
Abstract: Heterocyclic-substituted tricyclics of the formula ##STR00001## or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional single bond; represents an optional double bond, n is 0-2; Q is cycloalkyl, optionally substituted by R.sup.13 and R.sup.14; R.sup.13 and R.sup.14 are independently selected from (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl, --OH, (C.sub.1-C.sub.6)alkoxy, R.sup.27-aryl(C.sub.1-C.sub.6)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen and haloalkyl; or R.sup.13 and R.sup.14 together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms, Het is a mono- or bi-cyclic optionally substituted heteroaryl group; and B is a bond, alkylene, or optionally substituted alkenylene or alkynylene, wherein the remaining substituents are as defined in the specification, are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other cardiovascular agents is also claimed.
Inventor(s): Chackalamannil; Samuel (Califon, NJ), Clasby; Martin C. (Plainsboro, NJ), Greenlee; William J. (Teaneck, NJ), Wang; Yuguang (North Brunswick, NJ), Xia; Yan (Edison, NJ), Veltri; Enrico P. (Princeton, NJ), Chelliah; Mariappan V. (Edison, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Filing Date:Apr 10, 2007
Application Number:11/733,635
Claims:1. A compound represented by the structural formula ##STR00157## or a pharmaceutically acceptable stereoisomer or salt thereof, wherein: represents an optional double bond; ##STR00158## R.sup.1 is methyl; R.sup.2 is H; R.sup.3 is H; Het is, pyridyl, wherein a ring nitrogen can form an N-oxide group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by W; W is 1 to 4 moieties independently selected from the group consisting of phenyl or pyridyl, unsubstituted or substituted with R.sup.21; R.sup.10 is H, provided that when the optional double bond is present, R.sup.10 is absent; B is CH.dbd.CH--; X is --O--; Y is .dbd.O; R.sup.21 is 1 to 3 substituents independently selected from the group consisting of H, CN, --CF.sub.3, --OCF.sub.3, and halogen; R.sup.14 is independently selected from --(CH.sub.2).sub.n6NHC(O)OR.sup.16b, --(CH.sub.2).sub.n6NHC(O)R.sup.16b, --(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5, --(CH.sub.2).sub.n6NHSO.sub.2R.sup.16, --(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and --(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4; R.sup.16b is alkoxy, C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl-, R.sup.22--O--C(O)--(C.sub.1-C.sub.6)alkyl-, C.sub.3-C.sub.6-cycloalkyl, R.sup.28R.sup.29N--(CO)--(C.sub.1-C.sub.6)alkyl-, R.sup.28R.sup.29N--(CO)O--(C.sub.1-C.sub.6)alkyl-, -hydroxy(C.sub.1-C.sub.6)alkyl); R.sup.22 is H or (C.sub.1-C.sub.6)alkyl; and, R.sup.28 and R.sup.29 are independently selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, R.sup.27-aryl(C.sub.1-C.sub.6)alkyl, heteroaryl, heteroarylalkyl, hydroxy(C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, heterocyclyl, heterocyclylalky, halogen and haloalkyl; or R.sup.28 and R.sup.29 taken together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms.

2. A compound of claim 1 wherein the optional double bond is absent.

3. A compound of claim 1 selected from the group consisting of: ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## or a pharmaceutically acceptable stereoisomer, or salt thereof.

4. The compound of claim 1 wherein said salt is a bisulfate.

5. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.

7. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

8. A compound of the following formula: ##STR00166## or a pharmaceutically acceptable stereoisomer or salt thereof.

9. The compound of claim 8 wherein said salt is a bisulfate.

10. A pharmaceutical composition comprising an effective amount of a compound of claim 8 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising an effective amount of a compound of claim 8 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

12. A method of treating thrombosis, atherosclerosis, restenosis, hypedension, angina pectoris, arrhythmia, head failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 8.

13. A method of treating thrombosis, atherosclerosis, restenosis, hypedension, angina pectoris, arrhythmia, head failure, myocardial infarction, glomerulonephritis, thrornbotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition of claim 11.

14. A compound of the following formula; ##STR00167## or a pharmaceutically acceptable stereoisomer or salt thereof.

15. The compound of claim 14 wherein said salt is a bisulfate.

16. A pharmaceutical composition comprising an effective amount of a compound of claim 14 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising an effective amount of a compound of claim 14 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

18. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 14.

19. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition of claim 17.

20. A compound of the following formula: ##STR00168## or a pharmaceutically acceptable stereoisomer, salt or solvate thereof.

21. The compound of claim 20 wherein said salt is a bisulfate.

22. A pharmaceutical composition comprising an effective amount of a compound of claim 20 and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising an effective amount of a compound of claim 20 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

24. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 20.

25. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition of claim 23.

26. A compound of the following formula: ##STR00169## or a pharmaceutically acceptable stereoisomer or salt thereof.

27. The compound of claim 21 wherein said salt is a bisulfate.

28. A pharmaceutical composition comprising an effective amount of a compound of claim 21 and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising an effective amount of a compound of claim 21 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

30. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 21.

31. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia, comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition of claim 29.

32. A compound of claim 1 wherein R.sup.21 is selected from the group consisting of --CF.sub.3, F, Cl, and CN.

33. A compound selected from the group consisting of: ##STR00170## and the compounds of the following formula: ##STR00171## wherein R.sup.21 and R are as defined in Table 1: TABLE-US-00006 TABLE I Ex. R.sup.21 R 6 --CF.sub.3 --NHCO.sub.2-t-butyl 7 --CF.sub.3 --NHCO.sub.2CH.sub.3 8 --CF.sub.3 --NHCO.sub.2CH.sub.2CH.sub.3 9 --CF.sub.3 --NHCO.sub.2CH.sub.2CH.sub.2OCH.sub.3 10 H --NHCO.sub.2CH.sub.2CH.sub.3 11 F ##STR00172##

or a pharmaceutically acceptable stereolsomer, salt or solvate thereof.

34. A compound selected from the group consisting of the compounds of the following formula: ##STR00173## wherein Ar and R are as defined in Table 2: TABLE-US-00007 TABLE 2 Ex. Ar --R 34 ##STR00174## ##STR00175## 35 ##STR00176## ##STR00177## 36 ##STR00178## ##STR00179## 37 ##STR00180## ##STR00181## 38 ##STR00182## ##STR00183## 42 ##STR00184## ##STR00185## 43 ##STR00186## ##STR00187##

or a pharmaceutically acceptable isomer, salt or solvate thereof.

35. A compound selected from the group consisting of the compounds of the following formula: ##STR00188## wherein Ar and R are as defined in Table 3: TABLE-US-00008 Ex. Ar --R 44 ##STR00189## ##STR00190## 45 ##STR00191## ##STR00192## 46 ##STR00193## ##STR00194## 47 ##STR00195## ##STR00196## 48 ##STR00197## ##STR00198## 49 ##STR00199## ##STR00200## 50 ##STR00201## ##STR00202## 51 ##STR00203## ##STR00204## 52 ##STR00205## ##STR00206## 53 ##STR00207## ##STR00208## 54 ##STR00209## ##STR00210## 55 ##STR00211## ##STR00212## 56 ##STR00213## ##STR00214## 57 ##STR00215## ##STR00216## 58 ##STR00217## ##STR00218## 59 ##STR00219## ##STR00220## 60 ##STR00221## ##STR00222## 61 ##STR00223## ##STR00224## 62 ##STR00225## ##STR00226## 63 ##STR00227## ##STR00228## 64 ##STR00229## ##STR00230## 65 ##STR00231## ##STR00232## 66 ##STR00233## ##STR00234## 67 ##STR00235## ##STR00236## 68 ##STR00237## ##STR00238##

or a pharmaceutically acceptable stereoisomer or salt thereof.

36. The method of claim 6 further comprising administering to a mammal in need of such treatment an effective amount of one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

37. The method of claim 12 further comprising administering to a mammal in need of such treatment an effective amount of one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

38. The method of claim 18 further comprising administering to a mammal in need of such treatment an effective amount of one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

39. The method of claim 24 further comprising administering to a mammal in need of such treatment an effective amount of one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogret bisulfate.

40. The method of claim 30 further comprising administering to a mammal in need of such treatment an effective amount of one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel bisulfate.

41. A pharmaceutical composition comprising an effective amount of a compound of claim 3 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel.

42. A pharmaceutical composition comprising an effective amount of a compound of claim 8 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel.

43. A pharmaceutical composition comprising an effective amount of a compound of claim 9 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel.

44. A pharmaceutical composition comprising an effective amount of a compound of claim 10 in combination with one or more additional cardiovascular agents selected from the group consisting of aspirin and clopidogrel.

45. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition of claim 41.

46. A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, or cerebral ischemia comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition of claim 42.
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